This proposal aims to understand the immune response associated with spontaneous recovery of an acute hepatitis B virus (HBV) infection in HIV-infected and -uninfected persons to elucidate novel targets for immunotherapy that may allow chronic hepatitis B to be cured. These studies will also determine the immune response that is dysregulated in HIV infection to explain the greater rate of HBV persistence in HIV-infected persons. To complete the Aims, this proposal will study 188 men (66 HIV+) in the Multicenter AIDS Cohort Study who had acute hepatitis B while in follow-up and whose outcome of either spontaneous recovery or viral persistence has been determined. The first Aim focuses on the cytokine response and the interferon stimulated gene (ISG) response using a sample from a visit prior to infection, during the acute period of infection, and from a visit ~1 year aftr infection, when the outcome is determined. We will compare the cytokines/ISGs in those with and without spontaneous recovery, and whether these associations differ by HIV status. The second Aim focuses on elucidating differences in the T cell and B cell responses in those who do and do not recover from an acute infection. We will perform phenotyping of B cells from the same visits as in Aim 1. We will use intracellular cytokine staining to measure production of 5 cytokines to determine HBV- specific CD4+ and CD8+ T cell polyfunctionality from visits during and after acute infection. We will also correlate the cytokine responses to the T and B cell responses. All of these responses will be compared between HIV-infected and HIV-uninfected individuals to determine which responses are dysregulated. The third Aim will identify signaling interactions critical to HBV activation of the inflammasome and their role in spontaneous recovery. Inflammasomes are intracellular multiprotein complexes that release IL-1 B and IL-18 in response to danger signals. The effects of HIV on the signaling interactions will be determined by the addition of HIV to the experimental system. Innovative aspects of this project include: 1) The unique cohort of a large number of incident HBV infections where both spontaneous recovery and viral persistence occur in HIV-infected and HIV-uninfected individuals. 2) The ability to determine how HIV affects the various aspects of the anti-HBV immune response. To date, no one has been able to elucidate reasons for greater HBV persistence with HIV infection. 3) Although the antibody response is important to spontaneous recovery, this is the first study to investigate the B cell response to acute hepatitis B. 4) This s the first study to examine the polyfunctional T cell response to acute hepatitis B. 5) Use novel techniques to determine the role of the inflammasome in acute hepatitis B. The results from this proposal will facilitate future research to develop immunotherapies to cure hepatitis B, which is the leading cause of cirrhosis and hepatocellular carcinoma worldwide.